Pharmaceutical compositions comprising nebivolol

ABSTRACT

The present invention relates to pharmaceutical compositions comprising the selective beta 1 (B1)-receptor blocker nebivolol and/or a pharmaceutically acceptable salt thereof and a liquid vehicle comprising a semifluorinated alkane. The pharmaceutical composition of the present invention is useful for topical administration, for example ophthalmic topical administration and for use in the treatment of glaucoma, increased intraocular pressure, ocular hypertension and/or a symptom associated therewith.

BACKGROUND

The present invention relates to a pharmaceutical composition comprisingthe selective beta 1 (β₁)-receptor blocker nebivolol and a liquidvehicle comprising a semifluorinated alkane. The pharmaceuticalcomposition of the present invention is useful for topicaladministration, especially ophthalmic topical administration.

Pharmaceutical compositions in liquid form represent one of thepreferred types of drug formulations. Certain routes of topicaladministration, such as ophthalmic administration, typically require theliquid form in order to provide for an efficient delivery of the activeingredient and a patient-friendly mode of use.

The simplest type of liquid formulation is a solution, such as anaqueous solution of the active pharmaceutical ingredient. In certaincases, however, the development of a more complex formulation such as asuspension may be considered. For example, if a drug substance is verypoorly soluble in aqueous or other biocompatible solvent systems, or ifit is hydrolytically labile, a simple solution may not be feasible orrepresent the best choice.

Nebivolol belongs to a class of compounds named beta-blockers—a class ofmedications that are used to manage abnormal heart rhythms and toprotect the heart from a second heart attack after a first heart attack(secondary prevention). They are also widely used to treat high bloodpressure (hypertension).

Beta-blockers are also used in the treatment of glaucoma. Beta-blockersact by blocking beta-receptors at the level of the ciliary body and byreducing the aqueous humour production, thereby reducing the intraocularpressure (IOP). Two types of topical beta-blockers are available for usein the treatment of glaucoma: Non-selective beta-blockers, which blockboth beta 1 (β₁)- and beta 2 (β₂)-adrenoceptors; and cardio-selectivebeta blockers, which block only beta 1-receptors. Of the beta-blockerscommercially available, timolol, levobunolol, metipranolol and carteololare nonselective; betaxolol is a cardio-selective beta-blocker. The mostserious side effects of beta-blockers are the exacerbation of chronicobstructive airways disease with nonselective agents and theprecipitation of bronchospasm in some patients.

Nebivolol is a beta 1 (β₁)-receptor blocker with nitricoxide-potentiating vasodilatory effect used in treatment of hypertensionand also for left ventricular failure. It is highly cardio-selectiveunder certain circumstances. It is therapeutically used in form of aracemic mixture of its hydrochloride salt and displays negativeinotropic as well as direct vasodilating activity.

Increased intraocular pressure is a frequent disorder of the eye whichis often associated with optic nerve damage, in which case the diseaseis glaucoma. In the absence of optic nerve damage, the condition isreferred to as ocular hypertension.

Normal intraocular pressure is usually defined as being in the rangefrom 10 to 21 mmHg. The pressure results predominantly from balancebetween the production rate and the drainage rate of the aqueous humourin the eye. In addition, it is influenced by the corneal thickness andrigidity. The intraocular pressure typically fluctuates around about 15to 16 mmHg with amplitudes of up to 6 mmHg. For example, it usuallydecreases in the night due to a decreased production of aqueous humour.It also responds to various physiological factors such as exercise,heart rate, respiration, fluid intake, as well as certain types ofsystemic or topical drugs.

The aqueous humour is produced by the ciliary bodies of the eye, fromwhere it flows into the posterior chamber. The composition of theaqueous humour is very similar to that of blood plasma but differs fromthe latter by a lower protein content. Its main constituents are water(99%), electrolytes (inorganic ions to maintain the physiological pH),low amounts of albumin and β-globulins, ascorbate, glucose, lactate, andamino acids.

From the posterior chamber, the aqueous humour is distributed via thepupil of the iris into the anterior chamber of the eye. From here, itflows through the so-called trabecular meshwork, which is a spongytissue area lined by trabeculocytes whose main function is to drain thehumour into a set of tubes called Schlemm's canal, from where the humourenters the blood circulation. The humour flow from the trabecularmeshwork into the Schlemm's canal occurs via two different routes:either directly via the aqueous vein to the episcleral vein, orindirectly via collector channels to the episcleral vein by intrascleralplexus. This trabecular outflow pathway accounts for the major fractionof drained aqueous humour. In addition, there exists a second majordrainage pathway which is the uveoscleral outflow, which is relativelyindependent of the intraocular pressure and normally accounts for only 5to 10% of the aqueous humour drainage in healthy humans.

WO2008/136034 A2 describes the use of nebivolol or a salt or an esterthereof for the production of a medicament for lowering ocularhypertension. Nebivolol is formulated as an emulsion comprising, amongothers, soybean oil, egg yolk phospholipids and glycerol; as an oilsolution comprising soybean oil; and as an ophthalmic ointmentcomprising liquid paraffine and vaseline. In animal studies the animalsare treated with 100 μl 1% nebivolol in emulsion per eye.

D. Szummy et al. describe in Graefes Arch Clin Exp Ophthalmol (2014)252:917-923 experiments in which the effect of nebivolol on intraocularpressure is studied. Therein, solutions of nebivolol are administeredorally or topically into a conjunctival sac of a rabbits' eyes. Thenebivolol solutions are administered in concentrations of 0.1%, 0.5% and1% in a volume of 1 drop (50 μl). No indication is given, however,regarding the exact composition of the solution, especially not withregard to the solvent used.

WO2016/108130 A1 describes in the experimental section dispersions ofnebivolol hydrochloride in paraffin and the preparation of gelscomprising nebivolol hydrochloride for the treatment of diabetic wounds.

As an alternative to aqueous preparations, oily eye drops may beformulated if the respective drug substance is poorly water-soluble orprone to hydrolytic degradation. However, one of the major disadvantagesof all oil-based formulations for ophthalmic administration is that theyinherently have a negative impact on vision. Whether used as oilysolutions or oil-in-water emulsions, they exhibit a refractive indexwhich differs substantially from that of physiological tear fluid, whichleads to visual disturbances and blurring.

Moreover, oil-based formulations do not readily mix with tear fluid toform a homogenous liquid phase. Oily solutions are altogether immisciblewith the aqueous tear fluid, and the exact fate of an emulsion mixedwith tear fluid in a physiological setting is not completelypredictable. Further, oily carrier such as medium chain triglycerides(MCT) are known to cause a strong burning sensation upon instillation tothe eye.

Furthermore, oil-in-water emulsions are like aqueous solutions prone tomicrobial contamination during use. If they were to be presented inmulti-dose containers which are in principle more cost-efficient andconvenient for patients than single-use vials, they would have to bepreserved in order to ensure their microbiological quality. At the sametime, preservatives which can be used in ophthalmic formulations arepotentially damaging to the eye, in particular to the ocular surface,and should be avoided whenever possible.

It is therefore an object of the present invention to provide a novelpharmaceutical formulation comprising nebivolol and/or apharmaceutically acceptable salt thereof, which can be useful as amedicament, particularly for topical applications. It is a furtherobject of the present invention to find a treatment of increasedintraocular pressure, e.g. in association with open-angle glaucoma orocular hypertension, which overcomes at least one of the limitations ordisadvantages associated with prior art formulations.

A further object of the present invention is to provide liquidformulations of nebivolol and/or a pharmaceutically acceptable saltthereof which shows advantageous long-term stability.

A further object of the present invention is to provide liquidformulations of nebivolol and/or a pharmaceutically acceptable saltthereof which is effective in decreasing intraocular pressure at reducedtarget dosage.

Further objects of the invention will become clear on the basis of thefollowing description, examples, and patent claims.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a pharmaceuticalcomposition comprising:

-   (a) nebivolol and/or a pharmaceutically acceptable salt thereof, and-   (b) a liquid vehicle comprising a semifluorinated alkane.

In a second aspect, the present invention provides the composition ofthe first aspect of the invention for use as medicament, morespecifically for the treatment of glaucoma, increased intraocularpressure, ocular hypertension and/or a symptom associated therewith.

In a further aspect, the present invention provides a method for thetreatment of glaucoma, increased intraocular pressure, ocularhypertension and/or a symptom associated therewith, comprisingadministering to the eye of a subject in need thereof a pharmaceuticalcomposition according to the first aspect of the present invention.

In yet a further aspect, the present invention provides a kit comprisingthe pharmaceutical composition according to the first or second aspectof the invention and a container for holding the pharmaceuticalcomposition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the results of the measurementof the in-vivo intraocular pressure study according to Example 4 belowin which a suspension of nebivolol hydrochloride at a concentration of0.5% (w/v) in 1-perfluorohexyl-octane (F6H8) is administered.

FIG. 2 is a graphical representation of the results of the measurementof the in-vivo intraocular pressure study according to Example 4 belowin which a suspension of nebivolol hydrochloride at a concentration of1.0% (w/v) in 1-perfluorohexyl-octane (F6H8) is administered.

DETAILED DESCRIPTION OF THE INVENTION

It has been found by the inventors that the composition of the inventionsurprisingly overcomes several drawbacks of previously knownformulations of nebivolol.

In a first aspect, the present invention provides a pharmaceuticalcomposition comprising:

-   (a) nebivolol and/or a pharmaceutically acceptable salt thereof, and-   (b) a liquid vehicle comprising a semifluorinated alkane.

The pharmaceutical composition according to the present inventioncomprises as a first constituent (a) nebivolol and/or a pharmaceuticallyacceptable salt of nebivolol. The compound nebivolol as used herein isthe secondary amine1,1′-[Bis(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)]-2,2′-iminodiethanolof structural formula (Ia)

with the molecular formula C₂₂H₂₅F₂NO₄, molecular mass of 405.44 g/mol.The compound is also known as narbivolol or nebivololum and may be usedin the form of a mixture of diastereomers or in the form of singlediastereomers, such as, for example, the diastereomer of formula (Ib)

either in form of racemic mixtures of said diastereomers, or in the formof non-racemic mixtures or in the form of pure enantiomers, such as, forexample, in the form of the RSSS and SRRR enantiomers.

The term nebivolol as used herein may refer to a racemic mixture ofenantiomers, to any non-racemic, i.e. enantiomerically enrichedmixtures, as well as single diastereomers, or mixtures of diastereomersof the compound of formula (Ia), which may be used for the preparationof the pharmaceutical composition of the present invention as availableand in accordance with its intended use.

Nebivolol is commercially available in form of its free base asdescribed and shown by formula (Ia) and (Ib) above as well as in theform of pharmaceutically acceptable salts such as, for example nebivololhydrochloride of formula (Ic)

or other pharmaceutically acceptable addition salts.

The pharmaceutical composition may comprise nebivolol and/or apharmaceutically acceptable salt of nebivolol which means that thecomposition may comprise nebivolol in form of its free base as, forexample shown in formula (Ia) and formula (Ib), either alone or incombination with one or a mixture of different pharmaceuticallyacceptable salts of nebivolol. Furthermore, the present pharmaceuticalcomposition may comprise nebivolol in form of a salt, such as thehydrochloride of formula (Ic) either alone or in form of a mixture withother pharmaceutically acceptable salts of nebivolol as described above.

In a preferred embodiment of the present invention, however, thepharmaceutical composition of the present invention comprises nebivololin form of nebivolol hydrochloride salt. Preferably, the pharmaceuticalcomposition of the present invention comprises as component a) nebivololhydrochloride salt as a racemic mixture of the stereoisomer of formula(Ic) and its enantiomer.

Preferably, the nebivolol, nebivolol hydrochloride or anotherpharmaceutically acceptable salt of nebivolol as described above ispresent in the pharmaceutical compositions according to presentinvention in a therapeutically effective amount. The term “atherapeutically effective amount” as used herein refers to a dose,concentration or strength which is useful for producing a desiredpharmacological effect.

As a second constituent (b), the pharmaceutical composition according tothe present invention comprises a liquid vehicle comprising asemifluorinated alkane. Some of the key advantages of the presentinvention are brought about by the presence of a semifluorinated alkanein the composition, functioning as a liquid vehicle for forming either asolution, dispersion or a suspension. The term ‘semifluorinated alkane’as used herein means a compound in which a perfluorinated linear orbranched, preferably linear hydrocarbon segment is attached to a linearor branched, preferably linear hydrocarbon segment.

In preferred embodiments, however, the pharmaceutical composition of thepresent invention or, more specifically, the liquid vehicle of thepharmaceutical composition of the present invention comprises asemifluorinated alkane of the general formula (II)

CF₃(CF₂)_(n)(CH₂)_(m)CH₃   (II),

wherein the index n is an integer selected from 2 to 10, and m is aninteger selected from 2 to 10; or wherein n is an integer selected from3 to 7 and m is an integer selected from 4 to 7. Preferably, the liquidvehicle of the pharmaceutical composition of the present inventioncomprises a semifluorinated alkane of the general formula (II) whereinthe index n is an integer selected from 3 to 5, and m is an integerselected from 4 to 7.

Accordingly, said semifluorinated alkane as used in the composition ofthe present invention may preferably be selected fromCF₃(CF₂)₃—(CH₂)₄CH₃ (F4H5), CF₃(CF₂)₃—(CH₂)₅CH₃ (F4H6),CF₃(CF₂)₃—(CH₂)₆CH₃ (F4H7), CF₃(CF₂)₃—(CH₂)7CH₃ (F4H8),CF₃(CF₂)₄—(CH₂)₄CH₃ (F5H5), CF₃(CF₂)₄—(CH₂)₅CH₃ (F5H6),CF₃(CF₂)₄—(CH₂)₆CH₃ (F5H7), CF₃(CF₂)₄—(CH₂)₇CH₃ (F5H8),CF₃(CF₂)₅—(CH₂)₄CH₃ (F6H5), CF₃(CF₂)₅—(CH₂)₅CH₃ (F6H6),CF₃(CF₂)₅—(CH₂)₆CH₃ (F6H7), CF₃(CF₂)₅—(CH₂)₇CH₃ (F6H8),CF₃(CF₂)₇—(CH₂)₇CH₃ (F8H8), CF₃(CF₂)₅—(CH₂)₉CH₃ (F6H10). Morepreferably, said semifluorinated alkane may be selected fromCF₃(CF₂)₃—(CH₂)₄CH₃ (F4H5), CF₃(CF₂)₅—(CH₂)₅CH₃ (F6H6),CF₃(CF₂)₅—(CH₂)₇CH₃ (F6H8) and CF₃(CF₂)₅—(CH₂)₉CH₃ (F6H10). Mostpreferably, said semifluorinated alkane is one selected fromCF₃(CF₂)₃—(CH₂)₄CH₃ (F4H5) and CF₃(CF₂)₅—(CH₂)₇CH₃ (F6H8).

An alternative nomenclature for the specified semifluorinated alkanes asnoted in parentheses below and as may be further used herein, is basedon the general formula FnHm, wherein F means the linear perfluorinatedhydrocarbon segment, H means the linear non-fluorinated hydrocarbonsegment and n, m is the number of carbon atoms of the respectivesegment. For example, F4H5 may be used to denote1-perfluorobutyl-pentane or CF₃(CF₂)₃—(CH₂)₄CH₃ (which may be also,alternatively expressed as formula F(CF₂)₄(CH₂)₅H), which has a linearperfluorinated segment F with four carbons (n=4) and a linearnon-fluorinated hydrocarbon segment with five carbons (m=5).Furthermore, F6H8 may be used to denote 1-perfluorohexyl-octane orCF₃(CF₂)₅—(CH₂)₇CH₃ (which may be also, alternatively expressed asformula F(CF₂)₆(CH₂)₈H), which has a linear perfluorinated segment Fwith six carbons (n=6) and a linear non-fluorinated hydrocarbon segmentwith 8 carbons (m=8).

The pharmaceutical composition of the invention comprising of “a”semifluorinated alkane is to be understood herein, as comprising atleast one semifluorinated alkane of Formula (II) as described above.Optionally, however, the composition may comprise of more than one, forexample, a mixture of two or more semifluorinated alkanes of Formula(II), i.e. of any one of the semifluorinated alkane species as describedabove.

In a preferred embodiment, the pharmaceutical composition according tothe present invention comprises a semifluorinated alkane of Formula (II)which is selected from 1-perfluorohexyl-octane (CF₃(CF₂)₅—(CH₂)₇CH₃(F6H8)) and 1-perfluorobutyl-pentane (CF₃(CF₂)₃—(CH₂)₄CH₃ (F4H5)). In aparticular preferred embodiment of the present invention, thesemifluorinated alkane of Formula (II) is perfluorohexyl-octane(CF₃(CF₂)₅(CH₂)₇CH₃, F6H8).

In yet a further embodiment, the liquid vehicle of the pharmaceuticalcomposition of the present invention may consist of a semifluorinatedalkane of Formula (II) as specified above. In this context also, theterm “a” semifluorinated alkane is to be understood as at least onesemifluorinated alkane, but may also include the option of more thanone, or a plurality of semifluorinated alkane compounds. Accordingly, inone embodiment, the composition may consist of more than onesemifluorinated alkane of Formula (II) as specified above.

In another embodiment, the pharmaceutical composition according to thepresent invention comprises (a) nebivolol and/or a pharmaceuticallyacceptable salt thereof, and (b) a liquid vehicle comprising oressentially consisting of a semifluorinated alkane of general formula(II) as defined above, or a semifluorinated alkane selected from anyone, or combination of the semifluorinated alkane compounds as definedabove, and optionally, (c) one or more excipients.

As used herein, the term “consists” and related terms “consisting” or“consist” is to be understood as meaning that no other features, otherthan those prefaced by the term are present. In the context ofcompositions, if any other constituent or component is present in thecomposition other than those prefaced by such term, then it is presentonly in trace or residual amounts such as to confer no technicaladvantage or relevance in respect of the object of the invention, suchas may be further understood by the term ‘essentially” or“substantially” used in conjunction with these terms (e.g. ‘essentiallyconsisting of”). It is to be understood that isomeric or olefinicimpurities that originate from synthesis of semifluorinated alkanes andthat are present in only trace or residual amounts, as these cannot bequantitatively removed upon purification, and that do not confer anytechnical advantage or relevance in respect of the object of the presentinvention, do fall under the above definition of such other constituentor component. In contrast, the term ‘comprising” or related terms“comprises” or “comprise” in the context of the present compositions, isto be understood as meaning that other features, other than thoseprefaced by the term may be present in the composition.

In a further embodiment, the liquid vehicle of the presentpharmaceutical compositions as defined in any of the previousembodiments described above, preferably comprises a semifluorinatedalkane or optionally, a mixture of semifluorinated alkanes in an amountof at least 70% (w/w), 75% (w/w), 85% (w/w), 90% (w/w), 95% (w/w), 98%(w/w), 98.5% (w/w), 99% (w/w), 99.5% (w/w), 99.8% (w/w) or at least99.9% (w/w) of a semifluorinated alkane or a mixture of semifluorinatedalkanes as described above, with respect to the total weight of theliquid vehicle.

In some embodiments, the liquid vehicle of the present pharmaceuticalcomposition comprises at least 85% (w/w) of a semifluorinated alkane ora mixture of different semifluorinated alkanes. In a further embodiment,the liquid vehicle of the present invention essentially consists of 100%(w/w) of a semifluorinated alkane or mixture of semifluorinated alkanes.

The term “% (w/w)” as used herein and unless indicated otherwise refersto the amount of a component of a composition as a weight percentage inrelation to the total weight of the liquid vehicle of the presentpharmaceutical composition (with ‘w’ denoting weight).

In a particularly preferred embodiment, the liquid vehicle of thepharmaceutical composition according to the present invention comprises1-perfluorohexyl-octane (CF₃(CF₂)₅—(CH₂)₇CH₃ (F6H8)), preferably as theonly semifluorinated alkane present in the pharmaceutical composition.In a further preferred embodiment, the liquid vehicle of thepharmaceutical composition of the present invention essentially consistsof 1-perfluorohexyl-octane (F6H8). It is understood that a liquidvehicle essentially consisting of 1-perfluorohexyl-octane may comprisein trace or residual amounts isomeric or olefinic impurities (such as2-perfluorohexyl-octane or 1-perfluorohexyl-octene) originating fromsynthesis of F6H8 which cannot be quantitatively removed uponpurification.

In further embodiments, the liquid vehicle of the pharmaceuticalcomposition according to the present invention comprises1-perfluorobutyl-pentane (CF₃(CF₂)₃—(CH₂)₄CH₃ (F4H5)), preferably as theonly semifluorinated alkane present in the pharmaceutical composition.In a further preferred embodiment, the liquid vehicle of thepharmaceutical composition of the present invention essentially consistsof 1-perfluorobutyl-pentane (F4H5). It is understood that a liquidvehicle essentially consisting of 1-perfluorobutyl-butane may comprisein trace or residual amounts isomeric or olefinic impurities (such as2-perfluorobutyl-pentane or 1-perfluorobutyl-pentene) originating fromsynthesis of F4H5 which cannot be quantitatively removed uponpurification.

The liquid semifluorinated alkanes as described above are chemically andphysiologically inert, colourless and stable. Their typical densitiesrange from 1.1 to 1.7 g/cm³, and their surface tension may be as low as19 mN/m. Semifluorinated alkanes of the RFRH type are insoluble in waterbut also somewhat amphiphilic, with increasing lipophilicity correlatingwith an increasing size of the non-fluorinated segment.

The liquid vehicle of the pharmaceutical composition comprising asemifluorinated alkane as described above may also comprise a furthersolubilizing agent, such as one or more solvents or co-solvents. Inspecific embodiments, the liquid vehicle of the present pharmaceuticalcomposition comprises a co-solvent, preferably an organic co-solvent.

As used herein, the term “solubilizing agent” may denote a compound orsolvent or a co-solvent, preferably an organic solvent, that is misciblewith the semifluorinated alkane or the mixture of differentsemifluorinated alkanes of the present liquid vehicle and that enhancesor facilitates the solubility, or the dispersability of the activecomponent nebivolol in the chosen liquid vehicle comprising asemifluorinated alkane as described above.

Examples of potentially useful organic co-solvents include glycerol,propylene glycol, polyethylene glycol, and ethanol. However, theconcentration of the co-solvent should preferably be low relative tothat of the semifluorinated alkane or semifluorinated alkane mixture. Ifan organic co-solvent such as ethanol is used, it is recommendable tokeep it at or below a level of approx. 10% (w/w) or 5% (w/w) or even 3%(w/w) with regard to the total weight of the liquid vehicle. Morepreferably, the content of the co-solvent, more specifically of ethanolis from about 0.1 to about 2% (w/w), and most preferably not more thanabout 1% (w/w) with regard to the total weight of the liquid vehicle. Insome embodiments, the liquid vehicle of the present compositionaccording to the invention, however, are free of an organic co-solvent.

In other embodiments, the solubilizing agent, that may be optionallycomprised by the liquid vehicle of the present pharmaceuticalcomposition, may preferably be present in an amount of up to 3% (w/w),or preferably of up to 2.5% (w/w) with respect to the total weight ofthe liquid vehicle. In a preferred embodiment, the liquid vehiclecomprises a solubilising agent in amounts as low as up to 1% (w/w),preferably up to 0.5% (w/w) with respect to the total weight of theliquid vehicle. In another preferred embodiment, the liquid vehiclefurther comprises a solubilising agent in an amount of from about 2.5%to 0.5% (w/w), preferably of from about 1% to 0.5% (w/w) with respect tothe weight of the liquid vehicle.

In some embodiments, the solubilizing agent may be a liquid excipientsuch as, for example, a further organic co-solvent as described aboveand/or an oil selected from glyceride oils, liquid waxes and liquidparaffin, or an organic solvent exhibiting a high degree ofbiocompatibility.

Examples of potentially useful liquid excipients comprise oilyexcipients which may be used in combination with one or moresemifluorinated alkanes and include triglyceride oils, mineral oil,medium chain triglycerides (MCT), oily fatty acids isopropyl myristate,oily fatty alcohols, esters of sorbitol and fatty acids, oily sucroseesters or any other substance which is physiologically tolerated by theeye. In one of the preferred embodiment, the liquid vehicle comprises asolubilizing agent in form of a liquid excipient. Further examples ofpotentially useful solubilizing agents as used herein are organicsolvents. Preferred organic solvents include glycerol, propylene glycol,polyethylene glycol and ethanol. In yet further preferred embodiments,the liquid vehicle of the present pharmaceutical composition maycomprise ethanol as the solubilizing agent, preferably in an amount ofup to 1% (w/w), more preferably of up to 0.8% (w/w) and most preferredof up to 0.5% (w/w) with regard to the total weight of the liquidvehicle of the present pharmaceutical composition.

The pharmaceutical composition of the present invention comprises, as aconstituent a), the active ingredient nebivolol and/or apharmaceutically acceptable salt thereof, preferably nebivololhydrochloride, as described above. The present pharmaceuticalcomposition may comprise nebivolol and/or a pharmaceutically acceptablesalt thereof in an amount of from about 0.1% (w/v) to about 10% (w/v),or from about 0.1% (w/v) to about 5% (w/v), or from about 0.2% (w/v) toabout 3% (w/v), or from about 0.2% (w/v) to about 2% (w/v), or fromabout 0.3% (w/v) to about 1.5% (w/v), or from about 0.4% (w/v) to about1.25% (w/v), or from about 0.45% (w/v) to about 1.0% (w/v).

In preferred embodiments, the present pharmaceutical compositioncomprises nebivolol and/or a pharmaceutically acceptable salt thereof inan amount of from about 0.3% (w/v) to about 1.5% (w/v) or from about0.45% (w/v) to about 1.0% (w/v).

In a further preferred embodiment, the present pharmaceuticalcomposition comprises nebivolol hydrochloride in an amount of from about0.3% (w/v) to about 1.5% (w/v) or from about 0.5% (w/v) to about 1.0%(w/v).

Unless otherwise indicated, the term “% (w/v)” as used throughout hereinin connection with the present pharmaceutical composition denotes theamount of a component of a composition (such as, for example, nebivololor nebivolol hydrochloride) as a weight percentage in relation to thetotal volume of the composition (with ‘w’ denoting the weight and ‘v’denoting volume). For example, 0.05% (w/v) may be understood as relatingto 0.5 mg of a component in 1 mL of the composition, and 0.1% (w/v)would correspond to 1.0 mg of a component in 1 mL of the composition.

The active component nebivolol and/or a pharmaceutically acceptable saltthereof, preferably nebivolol hydrochloride as described above may bedissolved, dispersed or suspended in the liquid vehicle comprising asemifluorinated alkane as described below. Accordingly, the liquidpharmaceutical composition of the present invention may be in the formof a solution, preferably a clear solution or in form of a suspension.

In preferred embodiments, the pharmaceutical composition of the presentinvention is provided in form of a suspension. A suspension may bedefined as a type of a dispersion, a dispersion being a system having atleast one continuous (or coherent) phase and at least one discontinuous(or inner) phase which is dispersed in the continuous phase. In asuspension, the dispersed phase is in the solid state. The suspensionsuseful for practising the present invention are liquids, at least atphysiological temperature, which means that the continuous phase is aliquid. Typically, the suspensions are also liquid at room temperature.

Preferably, the present invention provides pharmaceutical compositions,in which particles of nebivolol and/or a pharmaceutically acceptablesalt thereof, preferably particles of nebivolol hydrochloride, as thedispersed phase are suspended in a liquid vehicle comprising asemifluorinated alkane, for example, a semifluorinated alkane of formula(II) as defined above as the continuous phase. Accordingly, in preferredembodiments of the present invention, the nebivolol and/or apharmaceutically acceptable salt thereof is suspended in the liquidvehicle comprising a semifluorinated alkane.

In further embodiment, the particles of nebivolol and/or apharmaceutically acceptable salt thereof, preferably of nebivololhydrochloride, are solid particles. In a further preferred embodiment,the particles, preferably the solid particles of nebivolol and/or apharmaceutically acceptable salt thereof, preferably of nebivololhydrochloride, substantially consist of nebivolol and/or a salt thereof,preferably of nebivolol hydrochloride.

In further embodiments, in the pharmaceutical composition of the presentinvention nebivolol and/or pharmaceutically acceptable a salt thereof,preferably of nebivolol hydrochloride, is suspended in the liquidvehicle at a concentration of from 0.3 to 1.5% (w/v) or preferably at aconcentration of from 0.5 to 1.0% (w/v).

As outlined above, in preferred embodiments, nebivolol and/or apharmaceutically acceptable salt thereof, preferably of nebivololhydrochloride, as the active ingredient of the present pharmaceuticalcompositions is incorporated in the form of suspended solid particles.In a particular embodiment, the suspended particles largely orexclusively consist of the active ingredient.

The particle size of the suspended nebivolol particles, preferablyparticles of nebivolol or nebivolol hydrochloride is preferably belowabout 100 μm, which means that most of the particles, e.g. at leastabout 90% thereof, have a size below 100 μm. Which type of particlediameter is considered as particle size will depend on the method usedfor particle size distribution, which in turn is selected to beappropriate for the type of solid material and the approximate sizerange. For example, laser diffraction or dynamic light scattering (alsoknown as photon correlation spectroscopy or quasi-elastic lightscattering) are appropriate methods for determining particle sizes inthe colloidal and low micron range, whereas sedimentation analysis,sieve analysis or photoanalysis may be selected for larger particlesizes.

In a further embodiment, at least about 90% of the suspended nebivololand/or a pharmaceutically acceptable salt thereof have a particle sizeof not more than about 20 μm, preferably of not more than about 15 μm.In a most preferred embodiment, at least 90% of the suspended particlesof nebivolol or a pharmaceutically acceptable salt thereof have a sizelower than about 10 μm or have size lower than about 5 μm. Especiallyfor ophthalmic administration, at least about 90% of the suspendedparticles of nebivolol and/or a pharmaceutically acceptable salt thereofhave a size lower than about 20 μm, preferably with at least about 90%of the suspended particles having a size of not more than about 15 μm,more preferably of not more than about 10 μm, or preferably of not morethan about 5 μm, as measured by state-of-the-art particle sizedistribution techniques (e.g. laser diffraction, dynamic lightscattering).

The pharmaceutical composition comprising nebivolol and/or apharmaceutically acceptable salt thereof, preferably nebivololhydrochloride, especially when suspended in a liquid vehicle comprisinga semifluorinated alkane display advantageous stability, especially withregard to the size of the suspended particles. As known from otherpharmaceutical compositions in form of suspensions, the suspendedparticles may aggregate, and depending on the forces by which theparticles attract each other, the aggregates thus formed may be ratherdifficult to resuspend. A further problem associated with that is thatin suspensions having non-uniform particle sizes there is a tendency forsmaller particles to gradually dissolve, whereas larger particles growthrough the deposition of dissolved material onto their surfaces(Ostwald ripening). In result, the particle size distribution of asuspension may become broader over time. Particles which grow beyond acertain size may be unsuitable for the intended use; for example, theymay occlude an injection cannula or, in case of ophthalmicadministration, irritate or even damage the ocular surface.

In contrast to this, it was found that the pharmaceutical composition ofthe present invention comprising nebivolol and/or a pharmaceuticallyacceptable salt thereof, preferably nebivolol hydrochloride, especiallywhen provided in form of a suspension can be stored for prolongedperiods of time without significantly changing their particle sizedistribution. Accordingly, the pharmaceutical composition of the presentinvention comprising nebivolol and/or a salt thereof, preferablynebivolol hydrochloride, in form of a suspension may be stored forextended periods of time, such as, for example for up to 1 year, or upto 6 months, or up to 3 months, or up to 2 months or up to 1 monthwithout significantly changing their particle size distribution of thesuspended particles. In exemplary embodiments, the present inventionprovides a pharmaceutical composition comprising nebivolol and/or a saltthereof, preferably nebivolol hydrochloride, in form of a suspensionwherein at least about 90% of the suspended particles of nebivololand/or a pharmaceutically acceptable salt thereof have a size of notmore than about 15 μm, after three weeks of storage at room temperature.The term room temperature as used herein is to be understood throughoutas a temperature in the range of 20 to 25° C.

In another exemplary embodiment, the present invention provides apharmaceutical composition comprising nebivolol and/or a salt thereof,preferably nebivolol hydrochloride, in form of a suspension wherein atleast about 90% of the suspended particles of nebivolol and/or apharmaceutically acceptable salt thereof have a size of not more thanabout 10 μm, after three weeks of storage at room temperature.

In contrast to some other suspensions known in prior art, thepharmaceutical compositions of the present invention when present in theform of a suspension usually require no surfactant, or, if at all, onlysmall amounts of surfactant, for their physical stabilisation. This is asignificant advantage as surfactants have a substantial potential forirritation and local toxicity, especially when administered to the eyeor by injection. According to one of the preferred embodiments, thepharmaceutical compositions of the invention are substantially free ofsurfactant. In a further embodiment, the total amount of surfactant orsurfactants, if more than one surfactant is incorporated, is not morethan about 5% (w/w), in particular not more than about 3% (w/w), orpreferably not more than about 1% (w/w), respectively, with regard tothe total weight of the final composition. In further preferredembodiments, the amount is not more than about 0.5% (w/w), or not morethan about 0.25% (w/w), respectively.

In this context, the semifluorinated alkanes as described herein,although they possess some amphiphilic properties due to their chemicalstructure which includes fluorinated and non-fluorinated alkyl (oralkylene) groups characterised by different degrees of lipophilicity,are not understood as being within the scope of surfactants.

The surfactants which are absent or only present in small amountsinclude non-ionic, cationic, anionic, and zwitterionic surfactants ascommonly used as excipients in various types of pharmaceuticalcompositions, e.g. as wetting agents, emulsifiers, dispersing agents,solubilisers and the like. Examples of surfactants which are consideredpotentially useful include tyloxapol, poloxamers such as Pluronic F68LFor Lutrol F68, Pluronic L-G2LF and Pluronic L62D, polysorbates such aspolysorbate 20 and polysorbate 80, polyoxyethylene castor oilderivatives, sorbitan esters, polyoxyl stearates, lecithins, purified orsynthetic phospholipids, and mixtures of two or more thereof.

The pharmaceutical composition of the invention may further compriseexcipients in range of up to about 10% (w/v), more preferably up toabout 5% (w/v), even more preferably up to about 2% (w/v) such as, forexample, non-fluorinated organic liquids, for example in order to modifythe properties of the liquid vehicle, such as the viscosity. Such otherliquid may be an oil selected from glyceride oils, liquid waxes, andliquid paraffin, or an organic solvent exhibiting a high degree ofbiocompatibility, or a mixture of more than one liquid excipients.

Examples of potentially useful oily excipients which may be used incombination with one or more semifluorinated alkanes as described abovemay include triglyceride oils (i.e. soybean oil, olive oil, sesame oil,cotton seed oil, castor oil, sweet almond oil), mineral oil (i.e.petrolatum and liquid paraffin), medium chain triglycerides (MCT), oilyfatty acids, isopropyl myristate, oily fatty alcohols, esters ofsorbitol and fatty acids, oily sucrose esters, or any other oilysubstance which is physiologically tolerated by the eye.

The composition of the present invention may, of course, comprisefurther pharmaceutical excipients as required or useful. Potentiallyuseful excipients include acids, bases, antioxidants, stabilisers,synergists, colouring agents and thickening agents. In a preferredembodiment, however, the liquid vehicle of the pharmaceuticalcomposition according to the present invention is free of any (further)excipients.

Furthermore, the invention provides a means of formulatingpharmaceutical compositions, preferably ophthalmic pharmaceuticalcompositions comprising nebivolol and/or a pharmaceutically acceptablesalt thereof, preferably nebivolol hydrochloride, which aremicrobiologically stable. This is due to the fact that semifluorinatedalkanes as comprised by the liquid vehicle of the present compositionsand as described above are not normally prone to microbialcontamination. Hence, it is possible to formulate preservative-freeophthalmic compositions which are better tolerable for many patients, inparticular patients suffering from an ophthalmic disease or condition.The preservative-free ophthalmic composition may be provided both inmulti-dose or single-dose format.

Accordingly, although the pharmaceutical composition of the presentinvention may comprise a pharmaceutically acceptable preservative, in apreferred embodiment, the pharmaceutical composition of the presentinvention is free of a preservative. This is especially useful when thecomposition of the present invention is provided not only in dosageforms for single use (single dosage forms), but especially in multipledosage forms with a plurality of doses.

In a further embodiment, water can also be present in the pharmaceuticalcomposition of the present invention, however, preferably in smallamounts of up 1.0% (w/w) or even of only up to 0.1% (w/w) or less, basedon the final composition (final dosage form). In a preferred embodiment,the pharmaceutical composition, preferably the liquid vehicle of thepharmaceutical composition of the present invention is essentially freeof water, whereas the residual water may be attributed to the potentialresidual water content of the active ingredient nebivolol and/or apharmaceutically acceptable salt thereof, especially nebivololhydrochloride. The term ‘essentially’ as used herein means if presentthen in trace or residual amounts such as to confer no technicaladvantage or relevance in respect of the object of the invention.

For example, 1-perfluorohexyl-octane (F6H8) or 1-perfluorobutyl-pentane(F4H5) as preferred semifluorinated alkanes in some embodiments of thepresent invention do not comprise any water, or have a water content ofno more than the maximal solubility of water in 1-perfluorohexyl-octaneor in 1-perfluorobutyl-pentane; for example 1-perfluorobutyl-pentane hasa water-content of less than 1.6×10⁻⁴ mg/ml as determined by methodsknown in the art for moisture analysis, such as Karl-Fischer titrationmethods.

In preferred embodiments, the pharmaceutical composition of the presentinvention essentially consists of nebivolol hydrochloride and asemifluorinated alkane selected from 1-perfluorobutyl-pentane (F4H5) and1-perfluorohexyl-octane (F6H8). In further embodiments, thepharmaceutical composition of the present invention essentially consistsof nebivolol hydrochloride and 1-perfluorohexyl-octane (F6H8), morespecifically of nebivolol hydrochloride suspended in1-perfluorohexyl-octane (F6H8).

In exemplary embodiments, the pharmaceutical composition of the presentinvention consists of from about 90 to about 99.99% (w/w), morepreferably from about 95 to about 99.9% (w/w), more preferably from 97to 99% (w/w) even more preferably from 98 to 99% (w/w) of the liquidvehicle comprising a semifluorinated alkane as described above,preferably a semifluorinated alkane selected from F4H5 and F6H8, basedon the weight of the final composition.

The pharmaceutical composition of the invention in form of liquidsuspensions may be prepared by conventional methods. In principle, thesolid nebivolol and/or nebivolol salt, preferably nebivololhydrochloride particles may be suspended in the liquid vehiclecomprising the semifluorinated alkane. Alternatively, the particles maybe precipitated in situ by adding a—typically organic—solution of theactive ingredient (and, optionally, one or more solid excipients) undercontrolled conditions to the semifluorinated alkane-based vehicle.

Conventional grinding or milling methods using standard equipment suchas a ball mill, hammer mill, roller mill, colloidal mill, jet mill, orthe like may be used If the particle size is to be reduced afterpreparation of a suspension, ultrasonication as well as various types ofhomogenisers may be used, such as colloid mills or high-pressurehomogenisers.

In a preferred embodiment, the particle sizes of the solid nebivololcompound in the composition according to the invention, when provided inform of a liquid suspension, are adjusted by first combining the drugparticles with a liquid vehicle comprising or consisting of asemifluorinated alkane such as described in any one of the aboveembodiments, followed by a step of milling or grinding according to anyof the above methods.

The pharmaceutical composition comprising a nebivolol compound insuspended form in a liquid vehicle comprising a semifluorinated alkaneprovides several advantageous properties over conventional, aqueous ornot semifluorinated alkane-based formulations, especially with respectto topical administration for ophthalmic use. For example, whenconventional perfluorinated compounds are used as liquid vehicles, thesuspensions tend to separate very rapidly by flotation of the dispersedphase, or by its sedimentation, depending on the relative densities ofthe dispersed phase and of the continuous phase. This is accompanied bya rapid formation of particle aggregates which may be dense and poorlyre-dispersible. Rapid flotation or sedimentation makes precise andreproducible dosing very challenging, if not impossible. For example, ifan ophthalmic suspension settles very rapidly after shaking, the firstdosing from a full container, if not withdrawn immediately upon shaking,will contain a lower-than-intended number of drug particles, unless thecontainer is held upside down, in which case more than the intendedquantity of drug particles will be dispensed. When the same container isnearly empty and the last doses are dispensed, the drug dose withdrawnper volume will be too high if it was low in the beginning, and viceversa.

Moreover, aggregates may easily obstruct the dispensing channels oropenings of containers and thereby lead to erroneous dosing. Ifdispensed from the container, they may cause irritation of theconjunctiva or of the cornea, depending on their size, shape andhardness.

In contrast, the semifluorinated alkane-based suspensions comprisingnebivolol and/or a pharmaceutically acceptable salt thereof according tosome embodiments of the invention remain finely dispersed andhomogeneous. If flotation or sedimentation takes place, it occursslowly, leaving sufficient time for the patient to withdraw a dose aftershaking the container. The formation of large aggregates is notobserved. After flotation or sedimentation, the drug particles areeasily re-dispersed by gentle shaking, and appear to largely retaintheir original particle size distribution. Preferably, thepharmaceutical composition of the present invention is a suspension,wherein the particles of nebivolol and/or a pharmaceutically acceptablesalt, preferably nebivolol hydrochloride, are re-dispersible by gentleshaking.

These properties of semifluorinated alkane-based suspensions ofnebivolol compounds result in superior pharmaceutical quality andperformance characteristics for the use of nebivolol in the treatment ofocular diseases. The level of convenience to the patient and/or healthcare provider is greatly increased. More importantly, the dosingaccuracy, i.e. precision and reproducibility of dosing, is greatlyimproved over other types of pharmaceutical suspensions. This will bringabout a more reliable therapeutic effect and a reduced risk of adverseeffects which result from overdosing.

A further surprising advantage of the presently described-compositionsin form of suspensions of nebivolol or nebivolol hydrochloride suspendedin a semifluorinated alkane is that they appear to form very smalldroplets when dispensed from a dropper such as an eye dropper. Withoutwishing to be bound by theory, it is believed that the small dropletsize is a result of an interplay of the semifluorinated alkane's uniqueproperties in terms of their density, viscosity, and surface tension. Inany case, it is believed that for topical administration into an eye asmall drop or volume of administration is highly advantageous as thecapability of the lacrimal sac to accept and hold fluid is extremelylimited. In fact, it is very common that the administration of aconventional eye drop formulation based on water or oil immediatelyleads to a discharge of a substantial fraction of the administeredmedicine as well as some tear fluid. At the same time, there is a riskthat some of the administered dose will be taken up systemically via thenasolacrimal duct. Hence, if an effective dose of an active ingredientcan be incorporated in a small volume of liquid which can be dispensedas a very small droplet, this should also contribute to a substantiallyincreased dosing reliability and reproducibility, thus enhancing thesafety and effectiveness of the therapy.

A yet further advantage of the invention which is based on the use ofsemifluorinated alkanes is that they can be designed or mixed for anoptimally adjusted evaporation behaviour after administration. Thus, itis possible to formulate an ophthalmic composition which deliversnebivolol or a salt thereof efficiently to the eye in such a way thatthe liquid vehicles is subsequently eliminated via evaporation. This isin sharp contrast to oily or perfluorinated eye drop vehicles which doeasily not evaporate and thus form non-physiological residues at thesite of administration, e.g. in the lacrimal sac.

In a second aspect, the present invention provides the pharmaceuticalcomposition according to the first aspect of the invention, namelypharmaceutical composition comprising:

-   (a) nebivolol and/or a pharmaceutically acceptable salt thereof, and-   (b) a liquid vehicle comprising a semifluorinated alkane-   for use as a medicament.

The pharmaceutical composition including all embodiments thereof asdescribed above for the first aspect of the invention is especiallyuseful for the therapy or prevention of diseases or conditions or anysymptoms associated therewith related to an eye of a subject, preferablyto an eye of a human subject.

The pharmaceutical composition of the present invention is especiallyuseful as an ophthalmic composition and may be administered to the eyeof a subject. More specifically, the pharmaceutical composition of thepresent invention may be administered topically to the eye of a subject,for example to the eye lid, eye sac, eye surface and/or to an ophthalmictissue of a patient. Preferably, the pharmaceutical composition of thepresent invention may be topically administered to an outer surface ofan eye of a patient or to an ophthalmic tissue which is readilyaccessible by the patient or by another person administering thepharmaceutical composition to the eye of the patient in need thereof.

The present pharmaceutical composition, especially when used as liquidof either low or higher viscosity (usually in the range of 1 to 3.5 mPas) may advantageously be administered in form of drops or by spraying orby injection. Most preferably, however, the liquid pharmaceuticalcomposition of the present invention, especially when provided in theform of a suspension, may be administered as drops, more specifically aseyedrops to be administered topically to the eye.

Depending on the extent of the disease, or whether or not both eyes ofthe patient to be treated are affected, the drops or eyedrops of thepresent ophthalmic pharmaceutical compositions may be administered toonly one eye or to both eyes of the patient. The present pharmaceuticalcomposition, provides droplet sizes when administered from conventionaldroppers, with a volume usually in the range from about 5 to about 15μl. This small droplet size usually facilitates the dropwiseadministration and, moreover, facilitates precise dosage of thepharmaceutical composition of the present invention. Accordingly, theophthalmic pharmaceutical composition of the present invention isadministered as single drops with a volume of about 5 to 15 μl per doseper eye, preferably with a volume of about 8 to 15 μl per dose per eye,more preferably with a volume of about 9 to 12 μl per dose per eye evenmore preferably with a volume of about 10 to 12 μl per dose per eye andmost preferably with a volume of about 11 μl per dose per eye.

Depending on the need, the composition according to the presentinvention is administered once (qd), twice (bid), three-times (tid) orfour-times (qid) per day per eye. Preferably, the composition accordingto the present invention is administered up to two-times per day pereye. In a preferred embodiment, the composition of the present inventionis administered twice (bid) daily. In a more preferred embodiment, thecomposition of the present invention is administered once (qd) daily.

The pharmaceutical composition according to the present invention isespecially useful in the treatment of glaucoma, increased intraocularpressure (IOP), ocular hypertension and/or a symptom associatedtherewith.

The present invention provides stable liquid pharmaceuticalcompositions, especially stable liquid suspensions comprising nebivololand/or a pharmaceutically acceptable salt thereof, preferably nebivololhydrochloride. These compositions can be topically administered andallow the administration of the active ingredient nebivolol in lowerdosages compared to known liquid formulations, thereby reducing the sideeffects associated to the active ingredient and the additionalcomponents of said known liquid formulations, in particular in thetreatment of glaucoma.

Based on this, the pharmaceutical composition for the use of the presentinvention allows for a significant reduction of droplet size and targetdose volume as described above associated therewith and therefore, asoutlined above, for a significant reduction of the total daily dose ofnebivolol administered for use in the treatment of glaucoma, increasedintraocular pressure, ocular hypertension and/or a symptom associatedtherewith. Accordingly, in preferred embodiments of the presentpharmaceutical composition for use in the treatment of glaucoma,increased intraocular pressure (IOP), ocular hypertension and/or asymptom associated therewith, nebivolol and/or a pharmaceuticallyacceptable salt thereof, preferably of nebivolol hydrochloride, issuspended in the liquid vehicle at a concentration of from 0.3 to 1.5%(w/v) or preferably at a concentration of from 0.5 to 1.0% (w/v). Insaid preferred embodiments, the liquid vehicle comprises or essentiallyconsists of a semifluorinated alkane, as defined by Formula (II) or anyone of the semifluorinated alkanes as defined above, such as asemifluorinated alkane selected from 1-perfluorobutyl pentane or1-perfluorohexyl octane. In further embodiments, the pharmaceuticalcomposition for the use according to the present invention may beadministered in a dose volume per eye of 10 to 12 μl wherein thenebivolol and/or a pharmaceutically acceptable salt thereof may besuspended in the liquid vehicle in a concentration of at least 0.3%(w/v).

In a preferred embodiment of the present invention, the (single) dose ofnebivolol and/or pharmaceutically acceptable salt thereof administeredper eye is from about 45 to about 120 μg, preferably from about 50 toabout 110 μg, even more preferably from about 55 to 110 μg. In a morepreferred embodiment, the pharmaceutical composition for use in thetreatment of glaucoma, increased intraocular pressure (IOP), ocularhypertension and/or a symptom associated therewith comprises a)nebivolol hydrochloride suspended in a semifluorinated alkane,preferably F6H8, wherein the (single) dose of nebivolol hydrochlorideadministered per eye is from about 45 to about 120 μg, more preferablyfrom about 50 to about 110 μg, even more preferably from about 55 to 110μg.

In another embodiment, the pharmaceutical composition for use in thetreatment of glaucoma, increased intraocular pressure (IOP), ocularhypertension and/or a symptom associated therewith, is administered tosubjects concomitantly suffering from dry eye disease and/orhypertension and/or cardiac related diseases. Thus, the pharmaceuticalcomposition for use in the treatment of glaucoma, increased intraocularpressure (IOP), ocular hypertension and/or a symptom associatedtherewith, is effective in not exacerbating comorbidities such as dryeye disease and/or hypertension and/or cardiac related diseases.

In another preferred embodiment, the pharmaceutical composition for usein the treatment of glaucoma, increased intraocular pressure (IOP),ocular hypertension and/or a symptom associated therewith is effectivein preventing side effects derived from the treatment of glaucoma orocular hypertension with non-selective beta blockers, wherein said sideeffects are exacerbation of chronic obstructive airways disease and/orbronchospasm and/or dry eye symptoms. In a third aspect, the presentinvention provides a method for the treatment of glaucoma, increasedintraocular pressure, ocular hypertension and/or a symptom associatedtherewith, comprising administering to the eye of a subject in needthereof a pharmaceutical composition according to the first aspect ofthe invention, namely a pharmaceutical composition comprising:

-   (a) nebivolol and/or a pharmaceutically acceptable salt thereof, and-   (b) a liquid vehicle comprising a semifluorinated alkane.

Accordingly, the method according to this aspect of the presentinvention comprises:

-   providing a composition comprising:    -   (a) nebivolol and/or a pharmaceutically acceptable salt thereof,        and    -   (b) a liquid vehicle comprising a semifluorinated alkane, and-   topically administering said composition to a surface of the eye of    the subject, or the patient.

It should be noted that for the method according to this aspect of theinvention all embodiments and preferred embodiments as described abovein connection with the other aspects of the invention applyrespectively. The subject, or patient in one embodiment may be a human.In another embodiment, the subject may be a veterinary subject orpatient.

The pharmaceutical composition according to the present invention offersthe possibility to administer and deliver, or to transport the beta1-receptor blocker nebivolol or a pharmaceutically acceptable saltthereof, especially nebivolol hydrochloride, directly to tissues orliquids of an eye of a subject or patient without the need of systemicapplication. Especially in cases in which the active compound nebivololor nebivolol hydrochloride is administered in form of particles,suspended in a liquid vehicle comprising a semifluorinated alkane asdescribed above, high concentrations of the active compound can bedelivered in relatively small volumes of the composition.

In yet a further aspect, the present invention provides for the use ofthe pharmaceutical composition according to the first aspect of theinvention, namely a pharmaceutical composition comprising:

-   (a) nebivolol and/or a pharmaceutically acceptable salt thereof, and-   (b) a liquid vehicle comprising a semifluorinated alkane

for the manufacture of a medicament for the treatment of glaucoma,increased intraocular pressure, ocular hypertension and/or a symptomassociated therewith.

In yet a further aspect, the present invention provides a pharmaceuticalkit comprising the composition as described above in connection with thefirst aspect of the invention, namely a pharmaceutical compositioncomprising:

-   (a) nebivolol and/or a pharmaceutically acceptable salt thereof, and-   (b) a liquid vehicle comprising a semifluorinated alkane,

and a container adapted for holding the pharmaceutical composition.Preferably, the container which contains the pharmaceutical compositionof the present invention further comprises a drop dispenser or deviceadapted for administering the pharmaceutical composition.

In specific embodiments of the kit according to this aspect of thepresent invention, the container has a dispensing means such as adropping device adapted for topically administering the composition tothe eye of a subject or patient, more specifically dispensing means fordropwise topical administration to a surface of the eye of a subject orpatient. In one of the preferred embodiments, the dispensing means isadapted to dispense the pharmaceutical composition dropwise in volumesof less than about 15 μl per drop. In further embodiments, thedispensing means is adapted to dispense drops having a volume of lessthan about 13 μl, 12 μl, or 11 μl, respectively. In particular, dropvolumes of less than 12 μl are presently considered very useful in viewof the limited holding capacity of one of the preferred sites ofadministration, the front of the eye. For the avoidance of doubt, suchsmall droplet sizes are primarily enabled by the incorporation of thesemifluorinated alkane (or semifluorinated alkanes) according to theinvention, and common droppers for eye drops which normally deliveraqueous drops of about 30 to 60 μl are capable of dispensing muchsmaller drops of semifluorinated alkanes-based formulations.

In the kit according to this aspect of the invention, the container mayhold a single dose or a plurality of doses of the present pharmaceuticalcomposition comprising nebivolol and/or a pharmaceutically acceptablesalt thereof and a liquid vehicle comprising a semifluorinated alkane asdescribed above.

Furthermore, the kit according to this aspect of the invention mayfurther comprise instructions for use of the container for dropwisetopical administration of the composition to a surface of the eye of apatient. The instructions or directions for use preferably comprised bythe kit according to this aspect of the invention may be in any formsuited to instruct the user how to perform the topical administration tothe affected eye of the patient or subject. It may be in any readable ortangible form, preferably in printed form or in any machine- orcomputer-readable form preferably in form of a machine-readable opticallabel such as, for example, a barcode or a QR-code. In a particularlypreferred embodiment the directions for use are provided in form of aninstruction leaflet, product or package insert or as an enclosed label.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the results of the measurementof the in-vivo intraocular pressure study according to Example 4 belowin which a suspension of nebivolol hydrochloride in1-perfluorohexyl-octane (F6H8) with a concentration of 0.5% (w/v) isadministered versus a formulation of timolol in aqueous solution with aconcentration of 0.5% (w/v). The graphs show the chronologicalprogression of the mean intraocular pressure (IOP) as measured in mmHg.

FIG. 2 is a graphical representation of the results of the measurementof the in-vivo intraocular pressure study according to Example 4 belowin which a suspension of nebivolol hydrochloride in1-perfluorohexyl-octane (F6H8) with a concentration of 1.0% (w/v) isadministered versus a formulation of timolol in aqueous solution with aconcentration of 0.5% (w/v). The graphs show the chronologicalprogression of the mean intraocular pressure (IOP) as measured in mmHg.

The following are numbered items comprised by the present invention:

-   1. A pharmaceutical composition comprising:    -   (a) nebivolol and/or a pharmaceutically acceptable salt thereof,        and    -   (b) a liquid vehicle comprising a semifluorinated alkane.-   2. The pharmaceutical composition according to item 1, comprising a    semifluorinated alkane of the formula (II)

CF₃(CF₂)_(n)(CH₂)_(m)CH₃   (II),

wherein n is an integer from 2 to 10, and m is an integer from 2 to 10;orwherein n is an integer from 3 to 5 and m is an integer from 4 to 7

-   3. The pharmaceutical composition of item 1 or 2, wherein the    semifluorinated alkane is selected from the group consisting of    1-perfluorobutyl-pentane (CF₃(CF₂)₃(CH₂)₄CH₃; F4H5) and    1-perfluorohexyl-octane (CF₃(CF₂)₅(CH₂)₇CH₃, F6H8).-   4. The pharmaceutical composition of any preceding item, wherein the    liquid vehicle comprises a co-solvent.-   5. The pharmaceutical composition of any preceding item, wherein the    liquid vehicle comprises at least 85% (w/w) of a semifluorinated    alkane or a mixture of different semifluorinated alkanes.-   6. The pharmaceutical composition of any preceding item, wherein the    liquid vehicle essentially consists of a semifluorinated alkane or a    mixture of different semifluorinated alkanes.-   7. The pharmaceutical composition of any preceding item, wherein the    nebivolol and/or a pharmaceutically acceptable salt thereof is    suspended in the liquid vehicle comprising a semifluorinated alkane.-   8. The pharmaceutical composition of any preceding item, wherein    nebivolol and/or a pharmaceutically acceptable salt thereof is    suspended in the liquid vehicle at a concentration of from 0.3 to    1.5% (w/v).-   9. The pharmaceutical composition of any preceding item, wherein    nebivolol and/or a pharmaceutically acceptable salt thereof is    suspended in the liquid vehicle at a concentration of from 0.45 to    1.0% (w/v).-   10. The pharmaceutical composition of any preceding item, comprising    nebivolol in the form of nebivolol hydrochloride.-   11. The pharmaceutical composition of any preceding item, wherein    the composition is essentially free of water and/or a preservative.-   12. The composition of any preceding item, wherein the composition    is free of further excipients.-   13. The composition of any preceding item, wherein the composition    is free of a surfactant.-   14. The pharmaceutical composition of any preceding item, wherein    the composition essentially consists of nebivolol hydrochloride and    a semifluorinated alkane selected from 1-perfluorobutyl-pentane    (F4H5) and 1-perfluorohexyl-octane (F6H8).-   15. The pharmaceutical composition of any preceding item, wherein    the composition essentially consists of nebivolol hydrochloride and    1-perfluorohexyl-octane (F6H8).-   16. The pharmaceutical composition of any of item 7 to 15, wherein    at least about 90% of the suspended particles of nebivolol and/or a    pharmaceutically acceptable salt thereof have a size of not more    than about 15 μm, or not more than about 10 μm.-   17. The pharmaceutical composition of any of item 7 to 16, wherein    at least about 90% of the suspended particles of nebivolol and/or a    pharmaceutically acceptable salt thereof have a size of not more    than about 10 μm after three weeks of storage at room temperature.-   18. The pharmaceutical composition of any preceding item for use as    a medicament.-   19. The pharmaceutical composition for use according to item 18, for    the treatment of glaucoma, increased intraocular pressure, ocular    hypertension and/or a symptom associated therewith.-   20. The pharmaceutical composition for use according to item 18 or    19, wherein the composition is administered to the eye of a subject.-   21. The pharmaceutical composition for use according to any of items    18 to 20, wherein the composition is administered topically to the    eye of a subject.-   22. The pharmaceutical composition for the use according to any of    items 18 to 21, wherein the pharmaceutical composition is    administered in a dose volume per eye, of 8 to 15 μl, preferably    from about 10 to 12 μl.-   23. The pharmaceutical composition for the use according to any of    items 18 to 22, wherein the pharmaceutical composition is    administered in a dose volume per eye of 10 to 12 μl and nebivolol    and/or a pharmaceutically acceptable salt thereof is suspended in    the liquid vehicle in a concentration of at least 0.3% (w/v).-   24. The pharmaceutical composition for the use according to any of    items 18 to 23, wherein nebivolol and/or a pharmaceutically    acceptable salt thereof is suspended in the liquid vehicle in a    concentration of from 0.45 to 1.0% (w/v).-   25. The pharmaceutical composition for the use according to any of    items 18 to 24, wherein the composition is administered up to two    times (bid) daily, preferably the composition is administered once    daily.-   26. A method for the treatment of glaucoma, increased intraocular    pressure, ocular hypertension and/or a symptom associated therewith,    comprising administering to the eye of a subject in need thereof a    pharmaceutical composition according to any one of items 1 to 17.-   27. The use of a pharmaceutical composition of any of items 1 to 17    for the manufacture of a medicament for the treatment of glaucoma,    increased intraocular pressure, ocular hypertension and/or a symptom    associated therewith.-   28. A kit comprising the pharmaceutical composition according to any    one of items 1 to 17 and a container for holding the pharmaceutical    composition.-   29. The kit according to item 28, wherein the container comprises a    drop dispenser for administering the pharmaceutical composition.-   30. The kit according to item 29, wherein the container comprises    dispensing means for dropwise topical administration to a surface of    the eye of a patient, said dispensing means preferably being adapted    to dispense the composition dropwise in volumes of less than about    15 μl.-   31. The kit according to any of item 28 to 30, wherein the container    holds a single dose or a plurality of doses of the composition of    any of claims 1 to 17.-   32. The kit according to any of items 28 to 31, further comprising    instructions for use of the container for dropwise topical    administration of the composition to a surface of the eye of a    patient.-   33. A method of treating glaucoma, increased intraocular pressure,    ocular hypertension or a symptom associated therewith, the method    comprising administering to an eye of a human with glaucoma,    increased intraocular pressure, ocular hypertension or a symptom    associated therewith, a composition comprising a) nebivolol and/or a    pharmaceutically acceptable salt thereof and b) a liquid vehicle    comprising a semifluorinated alkane, wherein the nebivolol and/or    pharmaceutically acceptable salt thereof is preferably suspended in    the liquid vehicle, wherein the amount of nebivolol and/or    pharmaceutically acceptable salt thereof administered in a single    dose per eye is from about 45 to about 120 μg, and wherein said    method is therapeutically effective in treating glaucoma, increased    intraocular pressure, ocular hypertension or a symptom associated    therewith.-   34. The method according to item 33, wherein the composition target    dose volume per eye is from about 8 to about 15 μl.-   35. The method according to any one of items 33 to 34, wherein the    composition target dose volume per eye is from about 10 to about 12    μl, preferably about 11 μl.-   36. The method according to any one of items 33 to 35, wherein the    composition comprises from about 0.45% to 1.0% w/v nebivolol and/or    a pharmaceutically acceptable salt thereof; and wherein the    nebivolol and/or a pharmaceutically acceptable salt thereof    administered in a single dose per eye is about 55 to about 110 μg    and the target dose volume per eye is about 11 μl.-   37. The method according to any of items 33 to 36, wherein the    semifluorinated alkane is selected from F6H8 and F4H5.-   38. The method according to item 37, wherein the semifluorinated    alkane is F6H8.-   39. The method according to any one of items 33 to 38, wherein the    composition is administered once daily.-   40. The method according to any one of items 33 to 39, wherein the    composition is substantially free of water and of preservative.-   41. The method according to any one of items 33 to 40, wherein the    composition comprises nebivolol in form of nebivolol hydrochloride.

The following examples serve to illustrate the invention; however, theseare not to be understood as restricting the scope of the invention.

EXAMPLES Example 1: Preparation of Nebivolol Suspensions

80 mg of nebivolol-hydrochloride (Sigma Aldrich; purity 100%) wereintroduced to a 25 mL vessel, filled with stainless steel balls,diameter 2 mm. Afterwards, 8 mL of 1-perfluorohexyl-octane (F6H8) wereadded, the vessel was closed and the milling was performed with aplanetary ball mill (PM 100, Retsch GmbH Germany) for 3 hours at 150 rpmwith an interval of 10 minutes (with change of direction). After themilling, the thereby formed suspension was transferred into a glassvial, shaken on a Vortex shaker for a minimum of 30 seconds, and sealed.Hereby, a 1.0% (w/v) Nebivolol-hydrochloride suspension (10 mg/mL) inF6H8 was obtained.

According to the same procedure a 1.0% (w/v) nebivolol-hydrochloridesuspension (10 mg/mL) in 1-perfluorobutyl-pentane (F4H5) was preparedusing 8 mL of F4H5 instead of F6H8.

The 10 mg/mL nebivolol suspension was stored in a glass vial at roomtemperature and the particle size distribution (PSD) was determined byLaser diffraction (HELOS 2412, performed with a 50 mL cuvette). Table 1below shows the particle size distributions for different Nebivololsuspensions after storage of one day at room temperature.

TABLE 1 Formulation X₅₀ (μM) X₉₀ (μm) X₉₉ (μm) Nebivolol hydrochloride3.58 8.69 13.20 10 mg/mL in F6H8 Nebivolol hydrochloride 3.48 8.28 12.8810 mg/mL in F4H5

X₅₀: median particle diameter determined on a volumetric basis, i.e. 50%by volume of the particles are smaller than the given diameter and 50%are larger.

X₉₀: particle diameter corresponding to 90% of the cumulative undersizedistribution determined on a volumetric basis, i.e. 90% of the particleshave a diameter lower than the given value X₉₀.

X₉₉: particle diameter corresponding to 99% of the cumulative undersizedistribution determined on a volumetric basis, i.e. 99% of the particleshave a diameter lower than the given value X₉₉.

Example 2: Stability Assessment of Nebivolol Suspensions

The Nebivolol suspensions as prepared according to Example 1 above werestored for 3 weeks at room temperature (20-25° C.). Following that, theparticle size distribution (PSD) was re-investigated by Laserdiffraction (Helios 2412, performed with a 50 mL cuvette) andmicroscopic analysis. Table 2 below shows the particle sizedistributions for different nebivolol suspensions after 3 weeks storageat room temperature (20-25° C.).

TABLE 2 Formulation X₅₀ (μM) X₉₀ (μm) X₉₉ (μm) Nebivolol hydrochloride3.81 9.71 15.35 10 mg/mL in F4H5 Nebivolol hydrochloride 3.46 8.12 12.5610 mg/mL in F6H8

Example 3: Dilution Experiments of Nebivolol Suspensions

Nebivolol suspensions in F4H5 or F6H8 with a concentration of 10 mg/mLwere prepared according to Example 1 above using Nebivolol-hydrochloride(CAS No. 152520-56-4; Chemos GmbH&Co. KG, Regenstauf). The suspensionswere diluted to concentration of 5 mg/mL by addition of an aliquot ofeither F4H5 or F6H8. The resulting suspensions were homogenous afterpreparation upon visual inspection and were stored at room temperaturefor 5 days. After that, the suspensions were separated and cloudy,however, resuspension of the settled suspensions was easily achieved.

After 5 days of storage at room temperature (20-25° C.) the particlesize distribution was determined by laser diffraction (HELOS 2412,performed with a 50 mL cuvette) as summarized in Table 3 below.

TABLE 3 Formulation X₅₀ (μM) X₉₀ (μm) X₉₉ (μm) Nebivolol hydrochloride3.59 7.32 16.46 10 mg/mL in F6H8 Nebivolol hydrochloride 3.46 8.23 22.955 mg/mL in F6H8

All Nebivolol hydrochloride suspensions in pure F4H5 and F6H8 withconcentrations of 5 mg/ml and 10 mg/mL, respectively, prepared by a ballmilling process as described above showed an optical appearance,homogeneity of the suspension and a suitability for re-homogenization ofthe settled suspensions which were ranked positive for preclinicalstudies in animal models.

The stability of the Nebivolol hydrochloride 5 mg/mL suspensionformulation in F6H8 was studied over 8 weeks. Samples were stored atroom temperature in closed glass vials. The appearance and the particlesize distribution, measured via microscope and DLS, did not change.

The stability of the corresponding Nebivolol hydrochloride 10 mg/mlformulation in F6H8 was conducted with the same design over 4 weeks. Nosignificant changes were detected.

Example 4: Measurement of Intraocular Pressure (IOP) in an Animal Study

An animal study utilizing normotensive dogs was carried out in order toassess the pharmacodynamics of Nebivolol with regard to its capabilityto lower the IOP (intraocular pressure) in comparison to thenon-selective beta-blocker Timolol which is administered in form of anaqueous solution. The study setup and design was as follows:

A total number of eight dogs were selected for participation in thestudy based on overall health, body weight, results of ophthalmicexaminations, response to IOP challenge, and the following criteria:

-   healthy, normal ocular surface;-   no invasive ocular procedures for at least one month prior to the    study; particularly procedures involving the cornea or ocular    anterior segment in general;-   no topical or systemic corticosteroid treatment for at least one    month;-   washout from prior topical ocular study medication commensurate with    the typical washout period used for clinical studies (at least one    week)

The study was performed according to the plan as summarized in Table 4below. The topical ocular dose of the respective Timolol-solution orNebivolol-suspension was administered to the central or superior part ofthe cornea via a micropipette and allowed to spread across the surfaceof the eye. After the dose was administered, the eye was allowed toclose naturally. Each animal was restrained for approximately one minuteto prevent rubbing of the eyes.

TABLE 4 Target Dose Target Topical Ocular Level Dose Measurement/ DoseRegime (μg/eye) Volume Dose Samples OD OS OD OS (μL/eye) FrequencyCollected Timolol 0.5% Nebivolol 150  55 11 (OS) QD for 8 IOP and (=5mg/mL)* hydrochloride in 30 (OD) days Irritation F6H8 (5 mg/mL) scoringTimolol 0.5% Nebivolol 150 110 11 (OS) QD for 8 IOP and (=5 mg/mL)*hydrochloride 30 (OD) days Irritation (10 mg/mL) scoring d Days IOPIntraocular pressure OD Right eye OS Left eye QD Once daily *aqueoussolution

In a first study, a suspension of Nebivolol hydrochloride in F6H8 (5mg/mL, translating to 4.6 mg/ml Nebivolol) was administered to the lefteye (OS) versus an aqueous solution of Timolol (5 mg/mL) which wasadministered to the right eye. Administration was done once daily for 8days. The intraocular pressure (IOP) was measured at 0 (immediatelypre-dose), 2, 4 and 6 hours post-dose on days 1, 2, 3, 6 and 7; at −1, 0(immediately pre-dose), 1, 2, 4, 6, 24 and 48 hours post-dose on day 8using a tonometer (TonoVet). Three readings per eye were taken. Theresults are summarized in FIG. 1 showing the development of the meanintraocular pressure (IOP) during treatment as described above.

In a second study, a suspension of Nebivolol hydrochloride in F6H8 (10mg/mL; translating to 9.2 mg/ml Nebivolol) was administered to the lefteye (OS) versus an aqueous solution of Timolol (5 mg/mL) which wasadministered to the right eye. Administration was done once daily for 8days. The intraocular pressure (IOP) was measured at 0 (immediatelypre-dose), 2, 4 and 6 hours post-dose on days 1, 2, 3, 6, and 7; at −1,0 (immediately pre-dose), 1, 2, 4, 6, 24 and 48 hours post-dose on day 8using a tonometer (TonoVet). Three readings per eye were taken. Theresults are summarized in FIG. 2 showing the development of the meanintraocular pressure (IOP) during treatment as described above.

Study Analysis

As shown in FIG. 1, the administration of 11 μl of 5 mg/ml nebivololhydrochloride in F6H8 (50.5 μg nebivolol, 0.12 μmol) resulted in adecrease of the intraocular pressure comparable to that of solutions of5 mg/ml timolol (150 μg timolol, 0.47 μmol) administered in a targetdose volume per eye of 30 μl.

The experimental data shows that by using a composition according to thepresent invention it is possible to achieve a decrease of the IOPcomparable to that of a commercial solution of a non-selective betablocker even with using a lower target dose of the active ingredient(0.12 mmol nebivolol vs 0.47 μmol timolol), translating to a reductionof the administered single dose per eye of about 74%. Furthermore, thelower target dose can be administered in a volume of, for example 11 μl,i.e. in a volume considerably lower than 30 μl, thus allowing areduction of the amount of composition which is expelled or which istaken up systemically.

As shown in FIG. 2, the administration of 11 μl of 10 mg/ml nebivololhydrochloride in F6H8 (100.9 μg nebivolol, 0.25 μmol) resulted in adecrease of the intraocular pressure comparable to that of solutions of5 mg/ml timolol (150 μg timolol, 0.47 μmol) administered in a targetdose volume per eye of 30 μl.

1. A pharmaceutical composition comprising: (a) nebivolol and/or apharmaceutically acceptable salt thereof, and (b) a liquid vehiclecomprising a semifluorinated alkane.
 2. The pharmaceutical compositionaccording to claim 1, wherein the semifluorinated alkane is asemifluorinated alkane of the formula (II)CF₃(CF₂)_(n)(CH₂)_(m)CH₃  (II), wherein n is an integer from 2 to 10 andm is an integer from 2 to 10; or wherein n is an integer from 3 to 5 andm is an integer from 4 to 7
 3. The pharmaceutical composition of claim1, wherein the semifluorinated alkane is selected from the groupconsisting of 1-perfluorobutyl-pentane (CF₃(CF₂)₃(CH₂)₄CH₃; F4H5) and1-perfluorohexyl-octane (CF₃(CF₂)₅(CH₂)₇CH₃, F6H8).
 4. Thepharmaceutical composition of claim 1, wherein the nebivolol and/or apharmaceutically acceptable salt thereof is suspended in the liquidvehicle comprising a semifluorinated alkane.
 5. The pharmaceuticalcomposition of claim 4, wherein the nebivolol and/or a pharmaceuticallyacceptable salt thereof is suspended in the liquid vehicle at aconcentration of from 0.3 to 1.5% (w/v).
 6. The pharmaceuticalcomposition of claim 4, wherein nebivolol and/or a pharmaceuticallyacceptable salt thereof is suspended in the liquid vehicle at aconcentration of from 0.45 to 1.0% (w/v).
 7. The pharmaceuticalcomposition of claim 1, wherein the nebivolol is in the form ofnebivolol hydrochloride.
 8. The pharmaceutical composition of claim 4,wherein at least about 90% of the suspended particles of nebivololand/or a pharmaceutically acceptable salt thereof have a size of notmore than about 15 μm.
 9. (canceled)
 10. A method for the treatment ofglaucoma, increased intraocular pressure, ocular hypertension and/or asymptom associated therewith, comprising administering to a patient inneed thereof a composition according to claim
 1. 11. The methodaccording to claim 10, wherein the composition is administered to theeye of a subject, preferably once daily.
 12. The method according toclaim 10, wherein the pharmaceutical composition is administered in adose volume per eye of 8 to 15 μl.
 13. The method according to claim 10,wherein the pharmaceutical composition is administered in a dose volumeper eye of 10 to 12 μl and wherein the composition comprises thenebivolol and/or a pharmaceutically acceptable salt thereof suspended inthe liquid vehicle in a concentration of at least 0.3% (w/v).
 14. Themethod according to claim 10, wherein the composition comprises thenebivolol and/or a pharmaceutically acceptable salt thereof suspended inthe liquid vehicle in a concentration of from 0.45 to 1.0% (w/v).
 15. Akit comprising the pharmaceutical composition according to claim 1, anda container for holding the pharmaceutical composition.